Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas.
BACKGROUND
Glucagon-producing tumors are either solitary neoplasms of the pancreas, occasionally associated with a glucagonoma syndrome, or multiple neoplasms associated with multiple endocrine neoplasia type 1 (MEN1). We observed a previously undescribed multicentric glucagon-producing tumor disease that is not related to MEN1.


METHODS
Pancreatic tissue from four patients showing multiple neuroendocrine microadenomas and in two cases also macrotumors were screened for hormones using immunohistochemical and morphometric methods. MEN1, von Hippel-Lindau, and p27 germ line and somatic mutation analysis was performed. Deletion of MEN1 (11q13), von Hippel-Lindau (3p25), and the centromere 11 and 3 gene locus was determined by fluorescence in situ hybridization. DNA copy number changes were studied using array comparative genomic hybridization.


RESULTS
The pancreatic tissue from the four patients contained more than 870 microadenomas and 10 macrotumors, all of which expressed exclusively glucagon and none of which showed evidence of malignancy. In addition, many islets were unusually large and showed glucagon cell hyperplasia. There was no clinical or molecular evidence of any hereditary tumor disease, and changes in the MEN1 gene were only seen in individual tumors. Array comparative genomic hybridization of one macrotumor and 20 pooled microadenomas revealed a homogeneous diploid chromosome set.


CONCLUSIONS
The findings are sufficiently distinctive to suggest a new neoplastic disease of the endocrine pancreas that we recommend calling glucagon cell adenomatosis. Clinically, this disease may be an incidental finding, or it may lead to a glucagonoma syndrome.
Henopp
Tobias
T
Department of Pathology, University of Tübingen, Liebermeisterstr. 8, 72076 Tübingen, Germany. Tobias.Henopp@med.uni-tuebingen.de
Anlauf
Martin
M
Schmitt
Anja
A
Schlenger
Regina
R
Zalatnai
Attila
A
Couvelard
Anne
A
Ruszniewski
Philippe
P
Schaps
Klaus-Peter
KP
Jonkers
Yvonne M H
YM
Speel
Ernst-Jan M
EJ
Pellegata
Natalia S
NS
Heitz
Philipp U
PU
Komminoth
Paul
P
Perren
Aurel
A
Klöppel
Günter
G
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005934:Glucagon; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human